Simple inexpensive boron electrophiles for direct arene borylation

Article abstract of DOI:10.1039/c1cc14226g

Electrophilic direct borylation is facilitated, and arene substrate scope enhanced, by using electrophiles derived from inexpensive reagents; specifically an amine, BCl₃ and AlCl₃.

Full text of DOI:10.1039/c1cc14226g

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COMMUNICATION
Simple inexpensive boron electrophiles for direct arene borylationw
Alessandro Del Grosso, Matthew D. Helm, Sophia A. Solomon, Dolores Caras-Quintero and
Michael J. Ingleson*
Received 13th July 2011, Accepted 5th October 2011
DOI: 10.1039/c1cc14226g
Electrophilic direct borylation is facilitated, and arene substrate
scope enhanced, by using electrophiles derived from inexpensive
reagents; specifically an amine, BCl3 and AlCl3.
ð1Þ
Aryl boronate esters (ArB(OR)2) are essential synthetic
building blocks, their ubiquity arising from ease of handling
optimized ratios, eqn. (1) produced the desired pinacolato-
boronate ester in 88% isolated yield post trans-esterification
with 2.1 equivalents of pinacol (PinH2). Borylation of the
slightly less activated arene N-TIPS-indole with Et3N as base
resulted in slower borylation. Substitution of Et3N for less
basic 2,6-lutidine in the first step enabled complete borylation
within 14 h in good yield (80% yield of C3-borylated product
isolated post trans-esterification on a 0.11 mol scale). However,
the large scale borylation of N-TIPS pyrrole using CatBCl
derived boron electrophiles was extremely sluggish.
combined with high efficacy in C–X (X = C, N, O) bond
forming reactions.1 The most expedient route to ArB(OR)2
is by direct C–H borylation, which circumvents undesirable
aryl-halides intermediates. Direct borylation was constrained
to the limited number of heterocycles and ortho-activating
arenes amenable to deprotonation.1,2 The development of
highly effective iridium catalysts for direct arene borylation
therefore represented a major breakthrough in this field.3
These catalysts display broad substrate scope and provide
aryl boronates in high yield with product regioselectivities
controlled by steric effects, or by heteroatom direction.3
Recently, we and others have reported a new synthetic
approach, intermolecular electrophilic borylation that is a
boron analogue of the Friedel–Crafts reaction.4–6 Inter-
molecular electrophilic direct borylation is complementary to
iridium catalysis, providing ArB(OR)2 with regioselectivities
controlled by arene electronic effects. This complementarity is
exemplified by the electrophilic borylation of 3-Br-N,N-dimethyl-
aniline and N-Me-indole occurring exclusively in the C4 and
C3 positions, respectively; in comparison iridium catalysis
proceeds with meta (in 1,3-disubstituted arenes) and C2 (of
five membered heterocycles) borylation.3,7,8 For electrophilic
borylation to be widely applicable a simple, inexpensive and
scalable system is required that offers expanded arene substrate
scope. Herein we report the realisation of this goal, the
development of new electrophiles that are readily synthesized
from an inexpensive amine, BCl3 and AlCl3. These borylating
agents have enhanced electrophilicity and are effective across a
range of scales.
A stronger boron electrophile that did not contain the
substituted catechol moiety (the large scale synthesis of CatBCl
is a significant time and cost factor) was envisaged based on
[X2B(amine)]+ (X = halide). Murakami et al., recently
reported the intramolecular borylation of 2-aryl-pyridines
and postulated the intermediacy of a [(2-aryl-pyridyl)BBr2]+
electrophile.9 Related [(pyridyl)BCl2]+ borenium cations10
have been previously observed in solution,11,12 and are attractive
potential borylating agents due to their simple synthesis
combined with the enhanced electrophilicity expected on
substituting two alkoxy groups in catecholato for chlorides.
[(2,6-lutidine)BCl2][AlCl4], compound 1, can be readily
synthesized in CH2Cl2 from stoichiometric combination of
BCl3 (1 M. in CH2Cl2 or heptane solution), AlCl3 and 2,6-
lutidine. Multinuclear NMR spectroscopy was consistent with
an ionic species with 11B NMR spectra displaying a single
resonance (d 46.9 ppm, pwhh = 120 Hz at 20 1C) consistent
with a [(pyridyl)BCl2]+ formulation.11,12 Confirmation of the
identity of 1 was forthcoming from X-ray diffraction on a
sample recrystallised from o-C6H4Cl2 (Fig. 1). The angles at
boron in 1 sum to 359.91, whilst all anion–cation contacts are
>3.8 A, consistent with a trigonal planar boron centre and an
ionic formulation, respectively. Whilst a number of weakly
stabilized boron–cations are known,6,13 compound 1 is the
first structurally characterized base adduct of a {B(halide)2}+
fragment. The pyridyl and Cl–B–Cl planes in 1 are effectively
orthogonal with an interplane angle of 84.81, orientated to mini-
mize repulsion between ortho methyls and chloride substituents.
This precludes pyridyl to boron p donation, which has been
The electrophilic borylation of N-Me-indole (on a 0.11 mol
scale) using less rigorous conditions than our previous report5
(N2 gas line, no glovebox, reagents weighed quickly in air at
Department of Chemistry, University of Manchester, Manchester,
M13 9PL, UK. E-mail: michael.ingleson@manchester.ac.uk;
Fax: +44 (0)161 275 4616; Tel: +44 (0)161 306580
w Electronic supplementary information (ESI) available: Experimental
details for all compounds and, crystallographic information for 1.
CCDC 837057. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc14226g
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12459–12461 12459

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a
Table 1 Borylation using electrophiles derived from BCl3
Isolated
Time yield
(h)b (%)c
Substrate
Product
Base
2,6-Lutidine 14
90
Fig. 1 ORTEP representation of 1, thermal ellipsoids at 50%
probability. Selected bond lengths (A) and angles (1): B1–N1 =
1.508(3), B1–Cl1 = 1.709(3), B1–Cl2 = 1.715(3), Cl1–B1–Cl2 =
122.89(17), Cl1–B1–N1 = 117.51(19), Cl2–B1–N1 = 119.60(20).
2,6-Lutidine 14
83
2,6-Lutidine
Me2NTol
Me2NTol
2
45d
previously calculated to provide significant stabilization in
the co-planar pyridyl/{BX2}+ geometry.14 Instead stabilizing
Cl - B p donation is indicated by the short B–Cl bond distances
in 1 (av. 1.712(3) A), in comparison the mixed amido/chloro
ligated borenium cation, [(C{N(2,6-iPr2C6H3)CH}2)BCl(NiPr2)]+,
where amidoN - B p donation will dominate has a longer
B–Cl bond distance of 1.787(3) A.13n Despite the low degree of
steric shielding in 1 compared to other borenium cations,13 it
persists as the major compound in CH2Cl2 even after >7 days at
20 1C.
14
14
76
60
2,6-Lutidine
Me2NTol
5
82
81
Compound 1 (or the active electrophile derived from 1)
displays the desired enhanced reactivity, completely borylating
N-TIPS-pyrrole in o14 h at 25 1C (Table 1). Esterification and
subsequent purification allowed the pinacolato boronate ester,
2m, to be isolated in high yield. This reaction was facile to
scale up, 22 g of 2m could be produced in one day in 90% yield
from inexpensive reagents available in bulk from commercial
suppliers. Compound 1 was also effective for the regioselective
borylation of N-Me-indole, N-Me-carbazole and N,N-Ph2-4-
Me-aniline (Ph2NTol, Table 2, 3m–5m). 2,20-dithiophene, 6,
was also regioselectively mono-borylated under ambient con-
ditions in the 5 position, with 6m isolated in high yield post
esterification. In contrast [CatB(amine)]+ based electrophiles
are insufficiently electrophilic for the borylation of
N-Me-carbazole and 2,20-dithiophene. Esterification of all
Aryl-BCl2 intermediates with pinacol in the presence of excess
base is facile with protodeboronation minimal. However 1 shows
no reaction with thieno-[2,3,b]-thiophene, 7, or alkyl-arenes at
20 1C. Thus compound 1 is (or forms) a less electrophilic
species than that derived from BCl3 and activated aluminium
(with AlCl3 as initiator). The latter borylates toluene at 30 1C,
with the electrophile postulated to be Cl2B(m-Cl)AlCl3.15–17
Seeking an even more reactive borylating agent 2,6-lutidine
was replaced with less basic N,N,4-trimethylaniline (Me2Ntol).
Combination of stoichiometric quantities of BCl3/AlCl3/Me2Ntol
in CD2Cl2 resulted in resonances attributable to BCl3 and
Cl3Al(Me2Ntol) along with one other product at +26.2 ppm in
the 11B NMR spectrum. The latter resonance is not consistent
with Cl3B(Me2Ntol) or [Cl2B(Me2Ntol)n]+ (n =1 or 2),18 and we
attribute it to a dynamic mixture of these species analogous to
that observed for [CatB(Me2NTol)][AlCl4].5 Attempts to confirm
a dynamic process by cooling an equimolar solution of BCl3/
AlCl3/Me2Ntol in CD2Cl2 failed to reach the slow exchange
18
2,6-Lutidine 18
86
83
Me2NTol
24
2,6-Lutidine 18
0
Me2NTol o0.5
81
Me2NTol
3
77
Me2NTol
Me2NTol
18
18
93
67
For exact stoichiometries see supporting information. b Time before
c
esterification. Isolated yields post pinacol esterification and purification.
a
d
Longer reaction times do not increase the yield of 4m.
regime (to ꢀ70 1C). However, addition of a second equivalent
of Me2NTol to this mixture resulted in the clean formation of the
two neutral adducts Me2NTol-BCl3 and Me2NTol-AlCl3, con-
sistent with a reversible halide transfer process.5
The combination of BCl3/AlCl3/Me2Ntol generates a highly
active borylating agent, usable on large scale. For example the
c
12460 Chem. Commun., 2011, 47, 12459–12461
This journal is The Royal Society of Chemistry 2011

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mono-borylation of N-Me-carbazole using BCl3/AlCl3/Me2Ntol
(1 : 1.1 : 1.3) required 14 h for complete borylation at a 0.1 mol
scale, producing 22 g of 4m post esterification (76% isolated
yield). Diborylation of N-Me-carbazole was realised using a
small excess, 2.5 : 2.75 : 2.625 BCl3 :AlCl3 :Me2NTol, with 4d
isolated in moderate yield. Application of related conditions to
Ph2NTol resulted in high yielding diborylation to produce 5d.
The di-borylation of 4 and 5 occurs despite the presence of
a –BCl2 moiety which will electronically deactivate the arene.19
The borylating species containing Me2NTol is more reactive
than [CatB(amine)]+ and 1, which do not diborylate 4 and 5.
The enhanced reactivity of BCl3/AlCl3/Me2Ntol also enables
the rapid borylation of thieno-[2,3,b]-thiophene, 7, which furn-
ished 7m in good yield post esterification (Table 1). Further-
more the BCl3/AlCl3/Me2Ntol reagent combination diborylates
2,20-dithiophene producing 5,50-(BCl2)2-2,20-dithiophene regio-
selectively in one step, whereas only monoborylation occurs even
using excess 1. Subsequent esterification produces 6d in high
isolated yield and purity (Table 1). Borylated carbazoles, triaryl-
amines and thiophenes are extremely important in organic
electronic applications, both in their own right,20 and as Suzuki–
Miyaura cross-coupling precursors, a process used extensively to
form extended p conjugated structures.21
To demonstrate the applicability of this process to signifi-
cantly less activated arenes m-xylene was borylated by
BCl3/AlCl3/Me2Ntol at 140 1C in C6H4Cl2 (m-xylene has
Mayr nucleophilicity values, N and sN, of ꢀ3.54 and 1.62,
respectivley).22 This produced two isomers post esterification,
the expected 1,3-Me2-4-BPin-C6H3 isomer and 1,3-Me2-
5-BPin-C6H3. The latter is formed from Lewis acid initiated
isomerisation of m-xylene.23 Pleasingly the enhanced borylating
reactivity does not reduce functional group tolerance or
regioselectivity; for example ether moieties remain compatible
(5-MeO-N-TIPS-indole, 8 is borylated at the C3 position and
esterified in high isolated yield) while 3-decyl-thiophene and
2-hexyl thiophene are both borylated regioselectively at C5
to provide 9m and 10m, respectively in good yield. It is
noteworthy that borylation of 3-decyl thiophene proceeds at
the less hindered C5 position and not at the electronically
favoured C2 position indicating that electrophilic borylation
using Me2NTol/BCl3/AlCl3 operates under synergic electronic
and steric control.
We gratefully acknowledge the Royal Society for the award
of a University Research Fellowship (M.J.I.), the EPSRC-KTA
(M.D.H.) and the University of Manchester.
Notes and references
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In summary, electrophilic borylation can be readily scaled
using less rigorous conditions and only requires inexpensive
materials commercially available in bulk quantities. Borylation
with BCl3 based electrophiles proceeds under ambient condi-
tions with pinacol-boronate esters isolated with excellent
regioselectivity and good yield. BCl3 derived boron electro-
philes are more reactive than [CatB(amine)]+ derivatives, able
to diborylate a range of arenes, whilst displaying comparable
functional group tolerance. Compounds 4d–6d are representative
of important precursors extensively used in the production of
organic electronic materials. Before this work synthetic routes
to these diborylated complexes were inefficient, proceeding via
aryl-halide intermediates and using cryogens and hard organo-
metallic reagents.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12459–12461 12461